Mechanisms of action of the anticonvulsant and psychotropic drug carbama- zepine are explored in seizure models and patients with affective disor- der. New findings based on biochemical, pharmacological, and cross- tolerance data suggest that carbamazepine exerts its anticonvulsant action in part through peripheral-type benzodiazepine receptors. A clinical trial with the peripheral-type agonist alpidem will be pursued. While GABA-B receptors were implicated in the antinociceptive effects of carbamazepine, the GABA-B agonist baclofen exacerbated illness in pa- tients leading to the suggestion that exploring GABA-B antagonist strate- gies would be fruitful. Carbamazepine has been discovered to increase TRH in the spinal fluid of patients who have lower levels of this com- pound compared with those in the euthymic state. These other data have led to a clinical trial of the utility of TRH as an acute treatment for patients with affective disorders. New studies also suggest important actions of carbamazepine on calcium channel flux mediated through NMDA receptors as revealed in cerebellar granule cell preparations. These data propel further exploration of agents with activities at this type of channel, such as ADCI, and at other types of calcium channels such as the L-type affected by the antagonist nimodipine. A variety of biological mechanisms at the level of immediate early genes, neurotransmitter receptors, and neuropeptides have been elucidated in the phenomenon of contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. These data suggest that loss of normal endogenous compensatory mechanisms may play a role in loss of efficacy in this model. Since tolerance development to carbamazepine is also impor- tant in its anticonvulsant, antinociceptive, and psychotropic clinical uses, this novel model promises to yield important information and targets for preventing or reversing loss of efficacy when it develops in the clinical arena.